Following the defeat and arrest of Archbishop Wolf Dietrich Raitenau by Bavarian forces in 1612, the cathedral chapter elected him to be the new Prince-Archbishop of Salzburg on 18 March 1612.[1] He received the Holy Orders from the hands of the Chiemsee bishop Ehrenfried von Kuenburg on October 7.[1] Raitenau gave his consent, hoping to be released from his custody at Hohensalzburg Castle; his hopes, however, were disappointed.

During his incumbency, the Archbishop took up the Counter-Reformation policies of his predecessor and had stern measures imposed on his subjects. According to the resolutions of the Council of Trent, he had the Catholic Corpus Christi fraternity established in order to fight "falsehood and heresy". Mark Sittikus also continued the redevelopment of his Salzburg residence: he employed the Italian architect Santino Solari to pursue the reconstruction of Salzburg Cathedral according to plans designed by Vincenzo Scamozzi, with the foundation stone of the new building being laid in 1614.[2] Nevertheless, the church building was not finished until in 1628 under. The archbishop also commissioned Santino Solari to build Hellbrunn Palace as his summer residence in the style of an ancient villa rustica, including extended gardens and its famous fountains.[2] He was thus a major figure in promoting Baroque architecture north of the Alps.[2] Moreover, under his rule, Monteverdi's opera L'Orfeo was performed on several occasions in Salzburg between 1614 and 1619.

Later in September, while Markus Sittikus awaited the arrival of the newly crowned Holy Roman Emperor on his way back to Vienna, he fell seriously ill with fever and died within fourteen days on 9 October 1619.[1] He was buried in the Franciscan cloister in Salzburg.